Glucagon has long been known to be effective in treating hypoglycaemia caused by insulin action. The hyperglycaemic effects of glucagon is a result of stimulating the breakdown of hepatic glycogen into glucose (glycogenolysis) and increasing the glucose production derived from amino acid precursors (gluconeogenesis) resulting in increased glucose output from the liver.
The commercially available glucagon for treatment of severe hypoglycaemia is supplied as a kit consisting of a vial with freeze dried glucagon and a disposable syringe prefilled with water (Eli Lilly and Novo Nordisk). Before use, glucagon has to be reconstituted by adding water from the syringe to the vial with glucagon. The vial must then be gently shaken until all glucagon has dissolved and the resulting solution should be drawn back into the syringe and injected to the person in need. In a severe hypoglycaemic event the patient is unconscious or semi-unconscious and is therefore dependent on an assisting person to administer glucagon.
The reconstitution step is considered troublesome by relatives to diabetics, and it delays or may even prevent treatment of severe hypoglycaemic events.
The main obstacle for a prefilled ready-to-use device is the inherent instability of glucagon. Solutions of glucagon form gels or fibrils within a few hours after dissolution. In addition, glucagon has an inherently low solubility in the pH range of 3-9. It contains several labile amino acids and the chemical stability of a glucagon composition is very poor, mainly due to deamidation, isomerization, oxidation and hydrolytic cleavage.
In order to enable the development of a prefilled ready-to-use device, a new non-fibrillating glucagon analogue needs to be developed. In addition, improved chemical stability of glucagon is required to enable a solution to be kept at room temperature for an extended period of time. Furthermore, such a glucagon analogue should have a fast onset of action (such as hyperglycaemic effect) after subcutaneous (SC) or intramuscular (IM) administration.